Cell and Developmental Biology Commons^™

Jab1 Negatively Regulates Pten And Promotes Resistance To Trastuzumab In Her2-Positive Breast Cancer, Thuy T. Vu

Dissertations & Theses (Open Access)

HER2-positive breast cancer, which is characterized by the over-expression of the HER2 onco-protein, accounts for approximately 20% of all breast cancer cases. Trastuzumab (Herceptin), the first targeted therapy approved for HER2-positive disease, potently prevents the activation of signaling pathways downstream of HER2 and significantly improves patients’ outcomes. However, resistance to trastuzumab is inevitable; such resistance can occur through reduced expression of PTEN protein.

Jab1 is over-expressed in 50% of primary cancers and 90% of metastatic tumors. Our lab previously showed that depletion of Jab1 in combination with trastuzumab treatment up-regulated PTEN in mouse xenografts refractory to trastuzumab. PTEN was not …

Mdm2-Mediated Degradation Of Sirt6 Phosphorylated By Akt1 Promotes Tumorigenesis And Trastuzumab Resistance In Breast Cancer, Umadevi Thirumurthi

Dissertations & Theses (Open Access)

Sirtuin6 (SIRT6) is one of the members of the Sirtuin family and functions as a longevity assurance gene by promoting genomic stability. It also regulates various cancer-associated pathways and was recently established as a bonafide tumor suppressor in colon cancer. This suggests that SIRT6 is an attractive target for pharmacological activation in cancer treatment, and hence, identification of potential regulators of SIRT6 would be an important and critical contribution towards cancer treatment. Here, we show that AKT1 phosphorylates SIRT6 at Ser³³⁸ and induces MDM2-SIRT6 interaction, priming SIRT6 for degradation via the MDM2-dependent ubiquitin-proteasome pathway. Blocking SIRT6 Ser³³⁸ phosphorylation …

Enhanced Breast Cancer Therapy With Nspefs And Low Concentrations Of Gemcitabine, Shan Wu, Jinsong Guo, Wendong Wei, Jue Zhang, Jing Fang, Stephen J. Beebe

Bioelectrics Publications

Chemotherapy either before or after surgery is a common breast cancer treatment. Long-term, high dose treatments with chemotherapeutic drugs often result in undesirable side effects, frequent recurrences and resistances to therapy. The anti-cancer drug, gemcitabine (GEM) was used in combination with pulse power technology with nanosecond pulsed electric fields (nsPEFs) for treatment of human breast cancer cells in vitro. Two strategies include sensitizing mammary tumor cells with GEM before nsPEF treatment or sensitizing cells with nsPEFs before GEM treatment.Breast cancer cell lines MCF-7 and MDA-MB-231 were treated with 250 65 ns-duration pulses and electric fields of 15, 20 or 25 …

Sorting Reality From What We Think We Know About Breast Cancer In Africa, Sulma I. Mohammed, Joe B. Harford

Department of Comparative Pathobiology Faculty Publications

Much attention has been paid to the features of breast cancer in Africa and the parallels between breast cancer in indigenous Africans and in African American women, including a shift toward earlier onset; a tendency toward poorer outcomes; and an increased likelihood for the tumors to be negative for the estrogen receptor (ER), the progesterone receptor (PR), and/or the human epidermal growth factor receptor-2 (HER2) [1,2]. One of the more aggressive forms of breast cancer is termed ‘‘triple negative,’’ i.e., ER2, PR2, HER22 [3]. Patients with triple negative breast cancer tend to be younger than patients with other forms of …

Nuclear Translocation Of Met Via Internet Mechanism, Mei-Kuang Chen

Dissertations & Theses (Open Access)

MET is one of the receptor tyrosine kinases (RTKs) that are overexpressed in malignant cancer types, including breast cancer. While RTKs are traditionally known for their roles in signaling transduction from the cell surface, recent studies have provided evidence demonstrating that most of RTKs can translocate into nucleus to regulate cellular processes in response to both ligand and stress stimulation. Oxidative stress is a common stress in cancer cells due to alteration of metabolism, and constitutive oxidative stress related to reactive oxygen species (ROS) has been observed in breast cancer cells. Here, we show that hepatocyte growth factor (HGF) as …

Brit1/Mcph1 Mediates The Dna Damage Response By Inducing P53 Stability And Promoting Atr Signaling, Edward Wang

Dissertations & Theses (Open Access)

The BRCT-repeat inhibitor of hTERT (BRIT1)/MCPH1 protein promotes the process of homologous recombination (HR) to repair DNA double strand breaks (DSBs). In response to DSBs, BRIT1 foci form at damaged sites, and recruits downstream repair proteins including 53BP1, MDC1, NBS1, and the SWI/SNF complex to the DSB region to promote DNA repair. BRIT1 copy number deficiency correlates with increased genomic instability in ovarian cancer specimens and breast cancer cell lines. Here, we propose that additional functions of BRIT1 include a direct interaction with the p53 tumor suppressor protein to promote p53 stability, and binding and recruitment of TopBP1 to sites …

The Role Of Mir-526b In Cox-2 Mediated Human Breast Cancer Progression And Induction Of Stem-Like Phenotype Via Ep4 Receptor Signaling, Erin O. Landman

Electronic Thesis and Dissertation Repository

Our laboratory previously established that aberrant expression of cyclo-oxygenase (COX)-2 promotes breast cancer progression and metastasis via multiple mechanisms, including stem-like cell (SLC) induction, owing to activation of the prostaglandin E2 receptor EP4. COX-2 expression was linked to up-regulation of miRNA-526b. We hypothesized that miR-526b is regulated by EP4 activity, and that miR-526b supports breast cancer progression and induction of SLCs. Using stably miR-526b transfected MCF-7 and SKBR-3 cells in functional assays, including tumorsphere formation in vitro and lung colony formation in vivo, we observed enhanced migration, invasion, proliferation, tumorsphere formation, and in vivo tumorigenecity compared to controls. EP4 …

Anti-Insulin Resistance Treatments Suppress Her2+ Breast Cancer Growth Via Altering Metabolism, Ping-Chieh Chou

Dissertations & Theses (Open Access)

Epidemiological studies have identified that type 2 diabetes mellitus (DM2) is a significant risk factor for carcinogenesis and cancer death, including breast cancer. Our previous finding in patients showed that anti-insulin resistance treatments are associated with improved HER2⁺ breast cancer survival of diabetic women. However, there were no transgenic mouse models to study the correlation and explain the detailed mechanism. We generated a mouse model of HER2⁺ breast cancer with DM2 by crossing leptin receptor point mutation (Lepr ^db/+) and MMTV-ErbB2 (neu) mice. The MMTV-ErbB2/Lepr ^db/db mice had a poor survival rate compared …

The Regulation Of Microrna Biogenesis By Ribosome-Interacting Proteins, Brian Pickering

Dissertations & Theses (Open Access)

MicroRNA (miRNA) are small, non-coding RNAs that affect gene expression through degradation of complementary mRNA targets or inhibition of translation. As they affect approximately 50% of all cellular processes, miRNA are tightly regulated by the cell through transcriptional and post-transcriptional mechanisms. Transcribed miRNA are capped and polyadenylated (referred to as pri-miRNA) which are cleaved by Drosha and DGCR8 to generate 60-90 nucleotide precursor miRNA. The precursors are cleaved again by Dicer and loaded into the RNA-induced silencing complex (RISC) of which Argonaute 2 is the functional component. Many of the proteins involved in miRNA biogenesis share a common role in …

Regulation Of Mammary Gland Development And Tumorigenesis By 14-3-3 Zeta, Sumaiyah Rehman

Dissertations & Theses (Open Access)

Signaling pathways that play critical roles in organ development are often aberrantly regulated during cancer initiation and progression. 14-3-3z is overexpressed in more than 40% of breast cancers and is associated with poor patient prognosis. Therefore, the function of 14-3-3z in cancer and normal mammary gland development was investigated utilizing multiple in vivo and in vitro approaches. 14-3-3z is a chaperone protein that interacts with a multitude of oncogenes and tumor suppressor genes, thereby functioning as a critical node in multiple oncogenic signaling networks. Mammary gland-specific 14-3-3z transgenic mouse models showed that 14-3-3z overexpression was sufficient to induce mammary tumorigenesis. …

The Effects Of Gold Nanorods On The Rate Of Apoptosis Of Triple Negative Breast Cancer Cells, Mattie E. Raiford

Honors College Theses

Triple negative breast cancer (TNBC) is a subtype of breast cancer that is most often found in African American females that is characterized by the lack of the progesterone receptor (PR), the estrogen receptor (ER), and the human epithelial growth factor receptor two (HER2).TNBC is a very aggressive form of breast cancer because it does not respond to hormone therapy, due to the lack of the three vital receptors. Since the current treatment is not affective, the project used porphyrin to specifically target cancer in the body because it has an increased affinity for many cancer types. Gold nanorods were …

Neurotrophins And Their Effects On Breast Cancer Cell Proliferation And Migration, Kayla Elise Minser

Open Access Theses

Cancer is a large health issue in all parts of the world. In the United States alone, approximately 1 in 4 deaths are cancer related. Breast cancer is a particularly prevalent form, accounting for a little over 14 percent of all cancer incidence. The largest obstacle to overcome for breast cancer morbidity is metastasis. Over 90 percent of all breast cancer related deaths are due to metastasis. Because metastasis is a complex, multi-step process, it is difficult to treat. A recent observation in the Kirshner lab has revealed a type of phenotypic plasticity, where migratory cancer cells have a neuronal-like …

Combating Resistance To Epidermal Growth Factor Recpetor Inhibitors In Triple Negative Breast Cancer, Julie Marie Madden

Wayne State University Dissertations

Triple negative breast cancer (TNBC) patients suffer from a highly malignant and aggressive cancer that lacks an effective targeted therapeutic. Although many TNBCs, both in vitro and in vivo, have increased expression of epidermal growth factor receptor (EGFR), EGFR targeted inhibitors, such as gefitinib (GEF), have yet to demonstrate efficacy. Using mass spectrometry to identify pathways that remain activated in the presence of GEF, we found that components of the mTOR signaling pathway remain phosphorylated. While inhibiting mTOR with temsirolimus (TEM) decreased mTOR signaling, EGFR signaling pathways remained activated and the TNBC cell lines continued to proliferate. However, dual treatment …

A Potential Mechanism For Extracellular Matrix Induction Of Breast Cancer Cell Normality, Robert D. Bruno, Gilbert H. Smith

School of Medical Diagnostics & Translational Sciences Faculty Publications

Extracellular matrix proteins from embryonic mesenchyme have a normalizing effect on cancer cells in vitro and slow tumor growth in vivo. This concept is suggestive of a new method for controlling the growth and spread of existing cancer cells in situ and indicates the possibility that extracellular proteins and/or embryonic mesenchymal fibroblasts may represent a fertile subject for study of new anti-cancer treatments.

The Lipogenic Phenotype Of Her2/Neu-Positive Breast Cancer Cells, Jan Martin Baumann

Legacy Theses & Dissertations (2009 - 2024)

Recent work has shown that HER2/neu-positive breast cancer cells rely on a unique Warburg-like metabolism for survival and aggressive behavior. These cells are dependent on fatty acid (FA) synthesis, show markedly increased levels of stored fats and disruption of the synthetic process results in apoptosis. Supplementation of the growth media with physiological concentrations of saturated FAs induces cell death, whereas HER2-normal cells are not affected. This is particularly interesting in the context of new epidemiological data showing that a diet rich in saturated FAs is positively correlated with the development of HER2-negative disease, but not HER2/neu-positive disease.

Sildenafil And Celecoxib Interact To Kill Breast Cancer Cells, Brittany Binion

Theses and Dissertations

Breast cancer is the second most commonly diagnosed cancer among American women and is responsible for the second highest number of cancer-related deaths. Targeted therapeutic agents sildenafil, a phosphodiesterase type 5 inhibitor, and celecoxib, a cyclooxygenase-2 inhibitor, have been used individually in conjunction with other chemotherapeutic agents to enhance cell killing in a variety of cancers. Sildenafil when combined with traditional chemotherapeutic drugs, such as the taxanes and anthracyclines, or celecoxib combined with traditional hormone therapies have been used to increase cytotoxicity and cell killing. The data presented here demonstrates that the novel combination of sildenafil and celecoxib work together …

Requirements Of Rab5 Activity In Highly Invasive Breast Cancer Cell Lines, Nicole Porther, M Alejandro Barbieri

Nicole Porther